Strategies to reduce morphine tolerance in cancer : evaluation of the bifunctional opioid UFP-505

摘要: Morphine is a gold-standard analgesic acting at MOP (μ) opioid receptors, producing analgesia and tolerance when administered chronically to patients (e.g.,cancer patients). If DOP (δ) receptors are blocked the same time that activated then with reduced results. UFP-505 (H-Dmt-Tic-Gly-NH-Bzl) synthetic pseudopeptide interacts (bifunctional). In series of different models, we have characterized pharmacological profile UFP- 505 evaluated its antinociceptive properties in vivo. Chinese Hamster Ovary (CHO) cells stably expressing human or presented full agonism ultra-low partial respectively. caused concentration-dependent internalization contrast morphine. Additionally, receptor similar agonist DPDPE. tail-flick assays using Wistar rats, acute intrathecal (i.t.) 10nmol produced strong antinociception, i.t. After 3 days repeated administration, did not produce tolerance, neuronal tissue treated animals, varying changes mRNA levels, morphine. model, induced internalization, whereas morphine failed internalize receptors. also novel CHO cell line both (produced as part this project), Collectively thesis has made significant contribution field that: 1) an extensive vitro vivo characterization made; 2) MOPagonist/DOP-partial shown antinociception no tolerance. Further work on bifunctional opioids may lead better understanding mechanisms ligands like good examples prototypes for further development.